WO2022068075A1 - Application de composé zju-37 dans la préparation d'un médicament pour la prévention et/ou le traitment de maladies hépatiques - Google Patents

Application de composé zju-37 dans la préparation d'un médicament pour la prévention et/ou le traitment de maladies hépatiques Download PDF

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Publication number
WO2022068075A1
WO2022068075A1 PCT/CN2020/136273 CN2020136273W WO2022068075A1 WO 2022068075 A1 WO2022068075 A1 WO 2022068075A1 CN 2020136273 W CN2020136273 W CN 2020136273W WO 2022068075 A1 WO2022068075 A1 WO 2022068075A1
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Prior art keywords
zju
compound
liver
preparation
application
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PCT/CN2020/136273
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English (en)
Chinese (zh)
Inventor
陈智
楼国华
刘艳宁
李爱春
葛田田
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浙江大学
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Publication of WO2022068075A1 publication Critical patent/WO2022068075A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the field of medicine, and specifically discloses the application of compound ZJU-37 in the preparation of medicaments for the prevention and/or treatment of liver diseases.
  • Acute and chronic liver injury is a common clinical disease. If it is not controlled and treated in time, it will develop into irreversible diseases such as severe hepatitis and liver failure. The fatality rate of acute liver failure is as high as 80% to 97%. %. At present, there is still no effective clinical treatment and drugs for severe hepatitis and liver failure. Therefore, it is urgent to develop new therapeutic drugs and develop new treatment methods and methods to improve the survival rate of severe hepatitis. Studies have shown that receptor-interacting protein kinase RIP1 is involved in various liver diseases. The use of RIP1 protein kinase inhibitors can reduce cell death and alleviate various inflammatory responses, but the specific mechanism is unclear.
  • RIP1 kinase inhibition is mainly aimed at neurodegenerative diseases and autoimmune diseases, including ulcerative colitis, psoriasis, rheumatoid arthritis and so on.
  • RIP1-involved cell death can promote tissue inflammation and damage, if not inhibit or even amplify tissue damage. Therefore, the development of targeting RIP1 kinase activity has clinical needs and broad application prospects.
  • the purpose of the present invention is to overcome the defects of the prior art and provide a new use of the compound ZJU-37.
  • the liver disease is liver injury, hepatitis, liver failure, liver tissue necrosis/apoptosis.
  • the liver injury may be acute liver injury.
  • the hepatitis may be severe hepatitis.
  • the liver failure may be acute liver failure.
  • the second aspect of the present invention provides new uses of the compound ZJU-37 of formula I, including the use of any one or more of the following medicaments.
  • the present invention discovers for the first time the application of compound ZJU-37 in the preparation of medicaments for the treatment of liver diseases, and opens up the application field of compound ZJU-37.
  • the present invention provides a new treatment mode and a treatment drug for serious liver diseases such as severe hepatitis and liver failure, and has obvious liver protection and treatment effects and obvious social benefits.
  • Figure 1 shows the comparison of the therapeutic effects of compound ZJU-37 and Nec-1s on liver injury and systemic inflammation in a mouse model of acute liver failure
  • Figure A and Figure B show the comparison of serum liver injury indexes ALT and AST levels in the LPS/GalN model group
  • the normal control group was significantly increased, and the serum ALT and AST levels in the treatment group were significantly decreased.
  • Compound ZJU-37 could significantly improve ALT and AST compared with commercial Nec-1s. Serum ALT and AST were reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s: 1053 ⁇ 107.7 vs. 724.8 ⁇ 119.5). And ZJU-37 can significantly reduce ALT (LPS/GalN vs.
  • Figure 2 shows the comparison of compound ZJU-37 and Nec-1s on liver pathological improvement and neutrophil infiltration in a mouse model of acute liver failure
  • Figures A and B represent the LPS/GalN model group
  • HE staining of liver tissue shows the liver Tissue necrosis and inflammatory cell infiltration were evident.
  • the compound ZJU-37 treatment group and the Nec-1s treatment group had significantly reduced liver tissue necrosis and inflammatory cell infiltration ( Figures C, D). Histopathological sections showed little necrosis of liver tissue and less inflammatory cell infiltration.
  • the immunohistochemistry of hepatic neutrophils by using Ly6G was consistent with HE staining.
  • FIG 3 shows the comparison of compound ZJU-37 and Nec-1s on liver cell death in a mouse model of acute liver failure; TUNEL-positive cells in the LPS/D-GalN model group were significantly increased compared with the normal control group (Panels A, B), while There was almost no TUNEL positive signal in the normal control group, indicating that a large number of liver cells underwent apoptosis in the model group.
  • the expression of TUNEL was significantly down-regulated in the treatment group; especially the compound ZJU-37 had the best effect, and histopathological sections of mouse liver tissue showed that the TUNEL signal was almost undetectable in liver tissue ( Figures C, D).
  • the compound ZJU-37 of the present invention belongs to the prior art, and can be prepared by the existing method.
  • Animal models are research tools to verify the effectiveness of new therapeutic drugs and new treatments.
  • the animal models used internationally to simulate liver failure include drug-induced liver failure models (acetaminophen model, LPS/GalN model, sulfur acetamide model, carbon tetrachloride model, etc.), acute hepatic ischemia model, partial hepatectomy model, etc.
  • the LPS/GalN model is an ideal animal model of liver failure because of its good reproducibility, no obvious extrahepatic toxicity, and the liver injury performance is close to clinical.
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated.
  • the LPS/GalN model was established for 6 hours, and the blood was collected by removing the eyeball for biochemical and CBA detection.
  • Figure A and Figure B show that the levels of serum liver injury indexes ALT and AST in the LPS/GalN model group were significantly higher than those in the normal control group, and the serum ALT and AST levels in the treatment group were significantly lower.
  • Compound ZJU ⁇ 37 Compared with commercial Nec-1s, it can significantly improve ALT, AST. Serum ALT and AST were reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s: 1053 ⁇ 107.7 vs. 724.8 ⁇ 119.5). And ZJU-37 can significantly reduce ALT (LPS/GalN vs.
  • compound ZJU-37 can better reduce liver injury and improve systemic inflammation in LPS/GalN-induced acute liver failure in mice at the same dose.
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated.
  • LPS/GalN modeling liver samples were collected for HE and immunohistochemical staining.
  • Figures A and B represent the LPS/GalN model group.
  • HE staining of liver tissue showed that liver tissue necrosis and inflammatory cell infiltration were obvious.
  • the compound ZJU-37 treatment group and the Nec-1s treatment group had significantly reduced liver tissue necrosis and inflammatory cell infiltration ( Figures C, D). Histopathological sections showed little necrosis of liver tissue and less inflammatory cell infiltration.
  • the immunohistochemistry of hepatic neutrophils by using Ly6G was consistent with HE staining.
  • compound ZJU-37 can better improve the liver pathology and reduce the infiltration of neutrophils in LPS/GalN-induced acute liver failure in mice under the same dose.
  • Example 4 Compound ZJU-37 inhibits apoptosis of liver tissue in LPS/GalN model mice
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated. After 6 hours of LPS/GalN modeling, liver tissue was collected for TUNEL staining.
  • TUNEL-positive cells in the LPS/D-GalN model group were significantly increased compared with the normal control group ( Figures A, B), while the normal control group had almost no TUNEL-positive signal, indicating that a large number of liver cells were apoptosis in the model group. Death.
  • the expression of TUNEL was significantly down-regulated in the treatment group; especially the compound ZJU-37 had the best effect, and histopathological sections of mouse liver tissue showed that the TUNEL signal was almost undetectable in liver tissue ( Figures C, D).
  • compound ZJU-37 can better improve liver cell death in LPS/GalN-induced acute liver failure in mice. This may also be a potential mechanism for the difference in the efficacy of the two drugs.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le domaine des médicaments. Une application d'un composé ZJU-37 de formule I dans la préparation d'un médicament pour la prévention et/ou le traitement de maladies hépatiques est divulguée. Après une recherche exhaustive et approfondie, une utilisation du composé ZJU-37 dans la préparation d'un médicament pour le traitement de maladies hépatiques a été découverte, ce qui élargit le champ d'application du composé ZJU-37. De plus, la présente invention concerne des procédés de traitement et des médicaments de traitement pour des maladies du foie majeures telles que l'hépatite grave et l'insuffisance hépatique, présente des effets de protection et de traitement du foie évidents, et présente des avantages sociaux significatifs.
PCT/CN2020/136273 2020-09-30 2020-12-14 Application de composé zju-37 dans la préparation d'un médicament pour la prévention et/ou le traitment de maladies hépatiques WO2022068075A1 (fr)

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CN202011063731.2A CN112263576A (zh) 2020-09-30 2020-09-30 化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用
CN202011063731.2 2020-09-30

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003042234A2 (fr) * 2001-11-14 2003-05-22 Novartis Ag Ligands non peptidiques du recepteur de la somatostatine
WO2005077344A2 (fr) * 2003-08-29 2005-08-25 The Brigham And Women's Hospital, Inc. Inhibiteurs de la necrose cellulaire
CN101674826A (zh) * 2005-12-20 2010-03-17 哈佛大学校长及研究员协会 化合物、筛选和治疗方法
CN106619619A (zh) * 2017-01-06 2017-05-10 浙江大学 化合物hubin‑1在制备肝脏炎症性疾病预防和/或治疗药物中的用途
CN107530350A (zh) * 2014-12-11 2018-01-02 哈佛理事会 细胞坏死抑制剂及相关方法
CN108191835A (zh) * 2018-01-09 2018-06-22 中国药科大学 一类新型的含吡咯环和吲哚啉结构rip1激酶抑制剂及其用途
CN110759895A (zh) * 2018-07-25 2020-02-07 浙江大学 新型rip1/rip3双靶点抑制剂及其在一药多靶疾病治疗中的用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003042234A2 (fr) * 2001-11-14 2003-05-22 Novartis Ag Ligands non peptidiques du recepteur de la somatostatine
WO2005077344A2 (fr) * 2003-08-29 2005-08-25 The Brigham And Women's Hospital, Inc. Inhibiteurs de la necrose cellulaire
CN101674826A (zh) * 2005-12-20 2010-03-17 哈佛大学校长及研究员协会 化合物、筛选和治疗方法
CN107530350A (zh) * 2014-12-11 2018-01-02 哈佛理事会 细胞坏死抑制剂及相关方法
CN106619619A (zh) * 2017-01-06 2017-05-10 浙江大学 化合物hubin‑1在制备肝脏炎症性疾病预防和/或治疗药物中的用途
CN108191835A (zh) * 2018-01-09 2018-06-22 中国药科大学 一类新型的含吡咯环和吲哚啉结构rip1激酶抑制剂及其用途
CN110759895A (zh) * 2018-07-25 2020-02-07 浙江大学 新型rip1/rip3双靶点抑制剂及其在一药多靶疾病治疗中的用途

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